Abstract
A wide range of approaches can be used to detect micro RNA (miRNA)–target gene pairs (mTPs) from expression data, differing in the ways the gene and miRNA expression profiles are calculated, ...combined and correlated. However, there is no clear consensus on which is the best approach across all datasets. Here, we have implemented multiple strategies and applied them to three distinct rare disease datasets that comprise smallRNA-Seq and RNA-Seq data obtained from the same samples, obtaining mTPs related to the disease pathology. All datasets were preprocessed using a standardized, freely available computational workflow, DEG_workflow. This workflow includes coRmiT, a method to compare multiple strategies for mTP detection. We used it to investigate the overlap of the detected mTPs with predicted and validated mTPs from 11 different databases. Results show that there is no clear best strategy for mTP detection applicable to all situations. We therefore propose the integration of the results of the different strategies by selecting the one with the highest odds ratio for each miRNA, as the optimal way to integrate the results. We applied this selection-integration method to the datasets and showed it to be robust to changes in the predicted and validated mTP databases. Our findings have important implications for miRNA analysis. coRmiT is implemented as part of the ExpHunterSuite Bioconductor package available from https://bioconductor.org/packages/ExpHunterSuite.
In order to improve the performance of existing technologies based on single crystal diamond grown by chemical vapour deposition (CVD), and to open up new technologies in fields such as quantum ...computing or solid state and semiconductor disc lasers, control over surface and bulk crystalline quality is of great importance. Inductively coupled plasma (ICP) etching using an Ar/Cl gas mixture is demonstrated to remove sub-surface damage of mechanically processed surfaces, whilst maintaining macroscopic planarity and low roughness on a microscopic scale. Dislocations in high quality single crystal CVD diamond are shown to be reduced by using substrates with a combination of low surface damage and low densities of extended defects. Substrates engineered such that only a minority of defects intersect the epitaxial surface are also shown to lead to a reduction in dislocation density. Anisotropy in the birefringence of single crystal CVD diamond due to the preferential direction of dislocation propagation is reported. Ultra low birefringence plates (<
10
−
5
) are now available for intra-cavity heat spreaders in solid state disc lasers, and the application is no longer limited by depolarisation losses. Birefringence of less than 5
×
10
−
7
along a direction perpendicular to the CVD growth direction has been demonstrated in exceptionally high quality samples.
We have measured the gamma-ray emission spectrum of the Moon using the data collected by the Large Area Telescope onboard the Fermi satellite during its first seven years of operation, in the energy ...range from 30 MeV up to a few GeV. We have also studied the time evolution of the flux, finding a correlation with the solar activity. We have developed a full Monte Carlo simulation describing the interactions of cosmic rays with the lunar surface. The results of the present analysis can be explained in the framework of this model, where the production of gamma rays is due to the interactions of cosmic-ray proton and helium nuclei with the surface of the Moon. Finally, we have used our simulation to derive the cosmic-ray proton and helium spectra near Earth from the Moon gamma-ray data.
In recent years, electron tomography has provided detailed three-dimensional models of mitochondria that have redefined our concept of mitochondrial structure. The models reveal an inner membrane ...consisting of two components, the inner boundary membrane (IBM) closely apposed to the outer membrane and the cristae membrane that projects into the matrix compartment. These two components are connected by tubular structures of relatively uniform size called crista junctions. The distribution of crista junction sizes and shapes is predicted by a thermodynamic model based upon the energy of membrane bending, but proteins likely also play a role in determining the conformation of the inner membrane. Results of structural studies of mitochondria during apoptosis demonstrate that cytochrome
c is released without detectable disruption of the outer membrane or extensive swelling of the mitochondrial matrix, suggesting the formation of an outer membrane pore large enough to allow passage of holo-cytochrome
c. The possible compartmentation of inner membrane function between the IBM and the cristae membrane is also discussed.
Network and systemic approaches to studying human pathologies are helping us to gain insight into the molecular mechanisms of and potential therapeutic interventions for human diseases, especially ...for complex diseases where large numbers of genes are involved. The complex human pathological landscape is traditionally partitioned into discrete “diseases”; however, that partition is sometimes problematic, as diseases are highly heterogeneous and can differ greatly from one patient to another. Moreover, for many pathological states, the set of symptoms (phenotypes) manifested by the patient is not enough to diagnose a particular disease. On the contrary, phenotypes, by definition, are directly observable and can be closer to the molecular basis of the pathology. These clinical phenotypes are also important for personalised medicine, as they can help stratify patients and design personalised interventions. For these reasons, network and systemic approaches to pathologies are gradually incorporating phenotypic information. This review covers the current landscape of phenotype-centred network approaches to study different aspects of human diseases.
Biofilm formation is a strategy of many bacterial species to adapt to a variety of stresses and has become a part of infections, contaminations, or beneficial interactions. In this study, we ...demonstrate that profound physiological changes permit
to switch from a floating to a sessile lifestyle, to undergo further maturation of the biofilm and to differentiate into the offensive or defensive features. We report that floating and biofilm cells are populations that differentiate metabolically, with members of each subpopulation developing different branches of certain metabolic pathways. Secondly, biofilm populations rearrange nucleotides, sugars, amino acids, and energy metabolism. Thirdly, this metabolic rearrangement coexists with: the synthesis of the extracellular matrix, sporulation, reinforcement of the cell wall, activation of the ROS detoxification machinery and production of secondary metabolites. This strategy contributes to defend biofilm cells from competitors. However, floating cells maintain a fermentative metabolic status that ensures a higher aggressiveness against hosts, evidenced by the production of toxins. The maintenance of the two distinct subpopulations is an effective strategy to face different environmental conditions found in the life styles of
.
Hyperosmolar solutions are widely used to treat raised intracranial pressure following severe traumatic brain injury. Although mannitol has historically been the most frequently administered, ...hypertonic saline solutions are increasingly being used. However, definitive evidence regarding their comparative effectiveness is lacking. The Sugar or Salt Trial is a UK randomised, allocation concealed open label multicentre pragmatic trial designed to determine the clinical and cost-effectiveness of hypertonic saline compared with mannitol in the management of patients with severe traumatic brain injury. Patients requiring intensive care unit admission and intracranial pressure monitoring post-traumatic brain injury will be allocated at random to receive equi-osmolar boluses of either mannitol or hypertonic saline following failure of routine first-line measures to control intracranial pressure. The primary outcome for the study will be the Extended Glasgow Outcome Scale assessed at six months after randomisation. Results will inform current clinical practice in the routine use of hyperosmolar therapy as well as assess the impact of potential side effects. Pre-planned longer term clinical and cost effectiveness analyses will further inform the use of these treatments.
Non-steroidal anti-inflammatory drugs (NSAIDs) are the most common cause of hypersensitivity reactions, with pyrazolones the most frequent drugs inducing selective reactions. Immediate selective ...hypersensitivity to pyrazolones is thought to be mediated by specific-IgE. Sensitivity of in vitro diagnostic tests is low and this may be due to the incomplete characterization of the structures involved. Here we investigated whether main metabolites of metamizole (dipyrone) in human could be involved in the immune response using the basophil activation test (BAT). We studied subjects with confirmed selective immediate hypersensitivity to metamizole and performed BAT with metamizole and its metabolites: 4-methylamino-antipyrine (MAA), 4-aminoantipyrine (AA), 4-acetylamino-antipyrine (AAA) and 4-formylamino-antipyrine (FAA). BAT results showed an increase of positive results from 37.5% to 62.5% using metamizole plus metabolites as compared with the BAT carried out only with the parent drug, demonstrating that metamizole metabolites have a role in the reaction and can induce specific basophil activation in patients with immediate hypersensitivity to this drug. Our findings indicate that pyrazolone metabolites are useful for improving the in vitro diagnosis of allergic reactions to metamizole.
•Equid gammaherpesviruses are commonly present in equine gastric mucosa.•Equid gammaherpesviruses can be detected in both ulcer and normal gastric tissue.•In situ hybridization (ISH) detected these ...viruses in gastric mucosal epithelium.
Horses commonly develop gastric mucosal ulcers, similar to humans, a condition known as equine gastric ulcer syndrome (EGUS) that can lead to poor performance and lost training time and care expenses. Unlike humans, however, an infectious bacterial cause of ulcers has not been conclusively identified. Herpesviruses, while well-established causative agents of diseases such as cold sores, genital lesions, and certain types of cancer, have also been implicated in the development of a subset of gastric ulcers in humans. The presence of equid herpesviruses in the gastrointestinal tract and their potential contribution to EGUS has not been evaluated. Here, we provide the first evidence of equid gammaherpesviruses 2 and 5 (EHV-2 and -5) within the epithelium of the gastric mucosa of horses. These viruses were initially detected by a nested PCR screen of gastric tissue samples obtained from client- and university-owned horses with and without ulcers; however, no association with EGUS was found in this limited sample set. We then validated a highly sensitive in situ hybridization (ISH) assay and used this assay to characterize the distribution of these viruses in necropsy gastric tissue samples from five racehorses. Analyses revealed frequent EHV-2 and EHV-5 co-infections within the gastric mucosal epithelium, regardless of the ulcer status. These results are the first to demonstrate the presence of equid gammaherpesviruses in the gastric mucosa of horses and warrants further investigation to determine the contribution of these viruses to the development of EGUS and/or other gastrointestinal diseases.
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